CN100554263C - The preparation method of strontium ranelate heptahydrate - Google Patents
The preparation method of strontium ranelate heptahydrate Download PDFInfo
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- CN100554263C CN100554263C CNB2006100147980A CN200610014798A CN100554263C CN 100554263 C CN100554263 C CN 100554263C CN B2006100147980 A CNB2006100147980 A CN B2006100147980A CN 200610014798 A CN200610014798 A CN 200610014798A CN 100554263 C CN100554263 C CN 100554263C
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Abstract
The present invention relates to the preparation method of strontium ranelate heptahydrate, the product that according to said method makes, water-content is 19.0-20.4%, related substance is lower than 0.5%.The strontium ranelate heptahydrate that adopts present method to make, stable under the room temperature situation, the water-content difference between batch is very little, preserves for a long time under physical environment, and its moisture, content, related substance all remain unchanged.It is characterized in that:, N-two (carboxymethyl) amino 1. with 2-[N]-3-cyano group-4-carboxymethyl thiophene-5-carboxylic acid four esters (b) were refluxing 5～6 hours in an amount of sodium hydroxide water-alcohol solution, and hydrolytic process keeps pH value more than 10; 2. and then add 20-60% ethanol, directly add the 2-2.5 times of molar weight strontium chloride aqueous solution subsequently, separate out crystallization, filter, dry; 3. add water and reflux, remove and wrap up small amounts of salts in the crude product, heat filtering is collected product.The present invention discloses the pharmaceutical composition that contains the strontium ranelate heptahydrate, be used for the treatment of the treatment of postmenopausal women's osteoporosis.
Description
Technical field
The present invention relates to the new preparation process and the pharmaceutical composition that contains it of strontium ranelate (Strontium ranelate) heptahydrate.This compound has the activity of treatment postmenopausal women osteoporosis.
Background technology
Strontium ranelate heptahydrate structural formula is as follows:
Strontium ranelate heptahydrate chemical name:
3-Thiopheneaceticacid，5-[bis(carboxymethyl)amino]-2-carboxy-4-cyano，strontium salt(1：2)heptahydrate
Be 5-[two (carboxymethyl) amino]-2-carboxyl-4-cyano group-3-thiophene acetic acid two strontium salt heptahydrates, has very valuable pharmacological activity, especially aspect the osteoporosis characteristic, it can suppress the heavily absorption of bone, can promote the formation of bone again, make this compound be used for the treatment of postmenopausal women's osteoporosis.
EP0415850 has described the preparation method and the therepic use of strontium ranelate and tetrahydrate, heptahydrate and eight hydrates.This patent is described in three kinds of methods that in the water alcohol solvent formula (b) are converted into formula (a).
(b) structural formula is as follows:
Wherein R1 and R2 can be identical or different, represent the alkyl (C1-6) of straight chain and side chain separately.
(b) compound that specifically refers to is 2-[N, N-two (carboxymethyl) amino]-3-cyano group-4-carboxymethyl thiophene-5-carboxylic acid tetra-ethyl ester.
(b) preparation method's reference Bull.Soc.Chim.France1975,1786-1792.
First method:, N-two (carboxymethyl) amino with 2-[N]-3-cyano group-4-carboxymethyl thiophene-5-carboxylic acid tetra-ethyl ester adds hydrolysis in the pure water blended sodium hydroxide solution, water layer with hcl acidifying after, remove sodium ion with sour sulfur acidic group plastic resin treatment again.Residue earlier with behind the ether with tetrahydrofuran (THF) or acetone recrystallization, generate 5-[two (carboxymethyl) amino]-2-carboxyl-4-cyano group-3-thiophene acetic acid (Ranelic acid), Ranelic acid and strontium chloride salify in water.In this way, can generate eight hydrates of Ranelic acid two strontium salt, dry under dry gas stream, generate heptahydrate, decompression (10mmHg) 55 ℃ of following dryings can obtain corresponding four hydrates, but the preparation method is loaded down with trivial details.
Second method: with 2-[N, N-two (carboxymethyl) amino]-3-cyano group-4-carboxymethyl thiophene-5-carboxylic acid tetra-ethyl ester adds hydrolysis in the pure water blended sodium hydroxide solution, after the hydrolysis with the alcohol and water evaporate to dryness, obtain the tetra-na salt solid, and then add the strontium chloride salify, but the tetra-na salt water absorbability is stronger, and actually operating also bothers;
The third method: with 2-[N, N-two (carboxymethyl) amino]-3-cyano group-4-carboxymethyl thiophene-5-carboxylic acid tetra-ethyl ester adds hydrolysis in the pure water blended strontium hydroxide solution, steam then and remove ethanol, the aqueous solution is heated to 100 ℃, heat filtering, residue gets Ranelic acid two strontium salt eight hydrates with tens milliliters of washings.By first method, Ranelic acid two strontium salt eight hydrates that 2,3 kinds of methods can be obtained change into seven water and four hydrates.
The applicant uses these methods, and the product related substance that makes higher (more than 2%), and the hydrate water-content instability that generates bring difficulty for the formulation of bulk drug quality standard and the preparation of preparation.Strontium ranelate is insoluble in most solvents, and purification operations is difficulty quite, so the product that makes with these methods is undesirable as the medicinal raw material medicine.
Summary of the invention
The inventor in the process of development, surprised discovery, the strontium ranelate heptahydrate that makes with method provided by the invention, stable under the room temperature situation, water-content difference between batch is very little, preserves for a long time under physical environment, and its moisture, content, related substance all remain unchanged.The present invention is based on above-mentioned discovery is accomplished.
The object of the present invention is to provide the preparation method of the strontium ranelate heptahydrate that is fit to suitability for industrialized production.
Another object of the present invention is to provide a kind of related substance is the strontium ranelate heptahydrate of 19.0-20.4% less than 0.5% water-content.
A further object of the present invention is to provide the pharmaceutical composition that contains the strontium ranelate heptahydrate.
For realizing above-mentioned purpose of the present invention, adopt following technical scheme:
The preparation method of strontium ranelate heptahydrate of the present invention is with the hydrolysis of water-ethanol mixed solvent, the strontium ranelate heptahydrate that makes with the strontium chloride salify then, water-content is very stable, its preparation method is: with 5-[two (carboxymethyl) amino]-2-carboxyl-4-cyano group-3-thiophene acetic acid tetra-ethyl ester and an amount of sodium hydroxide water-alcohol solution backflow 5-6 hour, keep pH value more than 10, get strontium ranelate tetra-na salt water-alcohol solution through hydrolysis, steam clean ethanol, get the strontium ranelate tetra-na salt aqueous solution, and then quantitatively add 20-60% ethanol, directly add the 2-2.5 times of molar weight strontium chloride aqueous solution subsequently, separate out crystallization, filter, dry, adding water refluxes, remove and wrap up small amounts of salts in the crude product, heat filtering is collected product, make related substance less than 0.5%, water-content is the strontium ranelate heptahydrate of 19.0-20.4%.
Adopt preparation method of the present invention, hydrolysis finishes, and steams except that behind the ethanol, the water evaporate to dryness is not made the tetra-na salt intermediate.But in the tetra-na salt aqueous solution, directly add strontium chloride aqueous solution salify, before adding strontium chloride, need in the aqueous solution of tetra-na salt, to add a certain proportion of ethanol, be the 20-60% of aqueous solution volume, the crystallization of separating out, filter, dry, add water and reflux, remove and wrap up small amounts of salts in the crude product, heat filtering is collected product.Surprisingly add a certain proportion of ethanol during salify, the strontium ranelate heptahydrate water-content of generation is very stable.
Strontium ranelate heptahydrate provided by the invention, the following test of process:
1.X-ray powder diffraction:
Instrument: Japanese D/MAX-2500X ray polycrystalline powder diffractometer of science
Target: the Cu-Ka radiation (
), 2 θ=2-40 °
Pipe is pressed: 40KV
Pipe stream: 100mA
Sweep velocity: 8 °/min
Filter disc: graphite monochromator
X-ray powder diffraction test result
2. dry weight-loss method is measured water-content
Precision takes by weighing the strontium ranelate heptahydrate, puts into vacuum drying oven, and 150 ℃ of vacuum-dryings are to constant weight.
Measurement result:
| Sequence number | 1 | 2 | 3 | 4 | 5 |
| Weight loss on drying (%) | 19.60 | 19.74 | 19.40 | 19.96 | 19.82 |
3. determination of related substances
Instrument: Agilent 1100 liquid phase systems
Chromatographic column: Diamonsil
TM(diamond) C
18Post
Moving phase: methyl alcohol-0.05% perchloric acid (35: 65)
Detect wavelength: 238nm
Column temperature: 30 ℃
Flow velocity: 1mL/min
Measurement result:
| Sequence number | 1 | 2 | 3 | 4 | 5 |
| Related substance (%) | 0.11 | 0.08 | 0.12 | 0.22 | 0.17 |
The heptahydrate of the present invention's development shows good physico-chemical property, have good quality, its purity is at least 99.5% (HPLC), and water content is relatively stable, and can be directly used in the preparation such as tablet, capsule and granule of medicine, be convenient to pharmaceutical preparation quality control and drug safety.
By the heptahydrate that the inventive method makes, can store considerable time under the condition to light, heat, wet no particular requirement, be convenient to produce, store.
Pharmaceutical composition provided by the invention contains strontium ranelate heptahydrate and pharmaceutically acceptable one or more pharmaceutical excipients.Described pharmaceutical composition is suitable for oral Preparation, comprises fast-release tablet, chewable tablet, dispersible tablet, effervescent tablet, enteric coated tablet etc. as tablet; Capsule comprises hard capsule, soft capsule; Granule comprises mix suspension grain, effervescent granule, enteric coated particles etc.; Oral suspensions; Syrup or the like.Preferred formulation is tablet, capsule, granule or the like.
According to the severity of the state of an illness and patient's age and body weight, once a day or gradation give 0.2～8g dosage.
Description of drawings:
Fig. 1 is a strontium ranelate heptahydrate crystalline XRD figure.
Embodiment:
The preparation method of strontium ranelate heptahydrate of the present invention is with reference to the EP0415850 disclosed method.
The present invention is described further below in conjunction with embodiment, and embodiment only is indicative, means that never it limits the scope of the invention by any way,
Embodiment 1: the preparation of strontium ranelate heptahydrate
Take by weighing 2-[N, N-two (carboxymethyl) amino]-3-cyano group-4-carboxymethyl thiophene-5-carboxylic acid tetra-ethyl ester 400g adds in the reaction flask, adds 3.6L1N sodium hydroxide solution and 3.6L ethanol, is heated to backflow, reaction 4h, keep the pH value more than 10 in the reaction process, cooling is filtered, filtrate decompression is steamed and is removed ethanol, quantitatively add 720ml ethanol in the aqueous solution, add the solution of 2 times of molar weight strontium chloride water then, separate out solid.Filter, cake layer washing 3 times is drained, and dries, and adds water 4L and refluxes, and heat filtering, boiling water are washed 3 times, drain, and room temperature is placed, and constant weight gets 440g.Weight loss on drying 19.82%, related substance 0.17%.Strontium ranelate heptahydrate crystalline XRD figure is seen Figure of description 1.
Embodiment 2: the preparation of strontium ranelate heptahydrate
Take by weighing 2-[N, N-two (carboxymethyl) amino]-3-cyano group-4-carboxymethyl thiophene-5-carboxylic acid tetra-ethyl ester, 500g adds in the reaction flask, add 4.5L1N sodium hydroxide solution and 4.5L ethanol, be heated to backflow, reaction 8h, keeping the pH value is 13, cooling, filter, filtrate decompression is steamed and is removed ethanol, adds 2250ml ethanol in the aqueous solution, add the solution of 2.5 times of molar weight strontium chloride water then, separate out solid.Filter, cake layer washing 3 times is drained, and dries, and adds water 5L and refluxes, and heat filtering, boiling water are washed 3 times, drain, and room temperature is placed, and constant weight gets 560g.Weight loss on drying 19.74%, related substance 0.08%.Strontium ranelate heptahydrate crystalline XRD figure is seen Figure of description 1.
Prepare 1000 bags of granule prescriptions, every bag contains activeconstituents 1g
The bulk drug 1246g of embodiment 1
Lactose 1800g
Microcrystalline Cellulose 1500g
Xylitol 100g
Sorbyl alcohol 100g
Methylcellulose gum 200g
Essence 100g
Preparation technology:
Main ingredient and auxiliary material are crossed 200 mesh sieves respectively.With the auxiliary material thorough mixing, take by weighing recipe quantity auxiliary material and main ingredient thorough mixing then earlier.Make softwood with 10%pvp water, 20 mesh sieves are granulated, 50 ℃ of dryings, and the whole grain of 20 mesh sieves sifts out fine powder, packing.
Claims (1)
1, the method for a kind of preparation formula (a) strontium ranelate heptahydrate:
It is characterized in that:
1. with 2-[N, N-two (carboxymethyl) amino]-3-cyano group-4-carboxymethyl thiophene-5-carboxylic acid four esters (b) were refluxing 4～8 hours in an amount of sodium hydroxide hydrous ethanol solution, and hydrolytic process keeps the pH value more than 10;
R wherein
1And R
2Can be identical or different, represent the alkyl of C1-C6 straight or branched separately;
2. after hydrolysis finishes to steam ethanol, obtain the Ranelic acid tetra-na salt aqueous solution, and then add 20%-60% ethanol, directly add the 2-2.5 times of molar weight strontium chloride aqueous solution subsequently, separate out crystallization, filter, dry;
3. add water and reflux, remove the small amounts of salts of wrapping up in the crude product, heat filtering is collected product, dries.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011107454A1 (en) | 2010-03-05 | 2011-09-09 | Chemelectiva Srl | Process for the preparation of a polymorph of strontium ranelate |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2921367B1 (en) * | 2007-09-26 | 2009-10-30 | Servier Lab | NEW PROCESS FOR THE SYNTHESIS OF STRONTIUM RANELATE AND ITS HYDRATES |
| CN101747316B (en) * | 2008-12-12 | 2013-09-25 | 重庆医药工业研究院有限责任公司 | High-purity strontium ranelate and preparation method thereof |
| CN102241663B (en) * | 2010-05-10 | 2013-02-13 | 山东方明药业集团股份有限公司 | Preparation method of strontium ranelate octohydrate |
| CZ2011320A3 (en) * | 2011-05-30 | 2012-12-12 | Zentiva, K.S. | Stable crystalline form of X strontium renelate |
| CN102321068B (en) * | 2011-08-01 | 2013-01-23 | 山东铂源药业有限公司 | Method for preparing strontium ranelate |
| CN102603708A (en) * | 2012-02-15 | 2012-07-25 | 吉林修正药业新药开发有限公司 | Preparation method of strontium ranelate |
| EP2641905A1 (en) | 2012-03-23 | 2013-09-25 | Urquima S.A. | Solid forms of strontium ranelate and processes for their preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011107454A1 (en) | 2010-03-05 | 2011-09-09 | Chemelectiva Srl | Process for the preparation of a polymorph of strontium ranelate |
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